We have previously hypothesized that enhanced sympathetic receptor sensitivity contributes to the etiology of type 2 diabetes mellitus (1). The goal of the present proposal is to determine if non-diabetic individuals, known to be at high risk for developing type 2 diabetes, show increased glycemic reactivity to behavioral and neuroendocrine challenges affecting the sympathetic nervous system. To this end, two groups who are at extraordinary risk for development of type 2 diabetes will be studied; Pima Indian Native Americans and women with a history of gestational diabetes. Two specific sets of studies are proposed. First, we will study the differential effect of mental arithmetic task on glucose, insulin, glucagon, catecholamines and cortisol in obese and lean subjects at high risk for diabetes and obese and lean appropriate controls. Data from these studies will allow us to determine if behavioral tasks differentially affect the metabolic responses of diabetes prone and diabetes resistant individuals and will give us some idea as to likely neuroendocrine mediators. Second, the differential glucose and insulin responses to adrenergic and opioid pharmacologic challenges which have been shown to differentiate normal individuals from diabetic patients and diabetes prone mice from diabetes resistant animals will be studied in both lean and obese subjects from the same high risk populations and in appropriate normal control subjects. If our hypothesis is confirmed, then glycemic responses to behavioral and/or neuroendocrine stimulation may be used as biologic markers to identify those individuals with a family history of diabetes who are at significant risk for the disease later in life.